Delivery of oligonucleotides to the body, such as an antisense-based therapeutics, poses several challenges. The binding affinity and specificity to a target, efficiency of cellular uptake, and nuclease resistance are all factors in the delivery and activity of an oligonucleotide-based therapeutic. For example, when oligonucleotides are introduced into intact cells they are attacked and degraded by nucleases leading to a loss of activity. Thus, a useful oligonucleotide should have good resistance to extra- and intracellular nucleases, as well as be able to penetrate the cell membrane.
Polynucleotide analogues have been prepared in an attempt to avoid their degradation, e.g. by means of 2′ substitutions (Sproat et al., Nucleic Acids Research 17 (1989), 3373-3386). However, such modifications often affect the polynucleotide's potency for its intended biological action. Such reduced potency may be due to an inability of the modified polynucleotide to form a stable duplex with the target RNA and/or a loss of interaction with the cellular machinery. Other modifications include the use of locked nucleic acids, which has the potential to improve RNA-binding affinity (Veedu and Wengel, RNA Biology 6:3, 321-323 (2009)), however, in vivo efficacy can be low. An oligonucleotide used as an antisense therapeutic should have high affinity for its target to efficiently impair the function of its target (such as inhibiting translation of a mRNA target, or inhibiting the activity of a miRNA target). However, modification of oligonucleotides can decrease its affinity and binding specificity, as well as its ability to impair the function of its target.
Thus, despite the variety of methods described for the delivery of oligonucleotides as a therapeutic, there is a need for improved chemical modifications for stable and efficacious oligonucleotide-based inhibitors.